New triazine derivatives as potent modulators of multidrug resistance.

A series of 70 triazine derivatives have been synthesized and tested for their capacity to modulate multidrug resistance (MDR) in DC-3F/AD and KB-A1 tumor cells in vitro, in comparison with verapamil (VRP), a calcium channel antagonist currently used in therapy as an antihypertensive drug, which also shows MDR modulating activity. Among the 12 selected compounds, 16 (S9788) showed high MDR reversing properties in vitro (300- and 6-fold VRP at 5 microM in DC-3F/AD and KB-A1 cells, respectively) and induced a strong accumulation of adriamycin. The relationship between the increase of ADR accumulation and the fold reversal induced by these compounds and their lack of effects on the sensitive DC-3F cells suggest that they act mainly by inhibiting the P-glycoprotein (Pgp) catalyzed efflux of cytotoxic agents, as already described for a majority of MDR modulators. In vivo, in association with the antitumor drug vincristine (0.25 mg/kg), 16 (100 mg/kg) increased the T/C by 39% in mice bearing the resistant tumor cell line P388/VCR. According to these interesting properties, 16 was selected for a clinical development because it was more bioavailable than 34, even though it was less active.

New purines and purine analogs as modulators of multidrug resistance.

A series of 36 purine and purine analog derivatives have been synthesized and tested for their ability to modulate multidrug resistance in vitro (P388/VCR-20 and KB-A1 cells) and in vivo (P388/VCR leukemia). Compounds were compared to S9788, a triazine derivative which has already shown some activity during phase 1 clinical trials and also a limiting cardiovascular side effect possibly linked to its calcium channel affinity. The fact that active compounds increase adriamycin accumulation in the resistant KB-A1 cells, and not in the sensitive KB-3-1 cells, suggests they act predominantly by inhibiting the P-glycoprotein-catalyzed efflux of cytotoxic agents. No direct relation was found between the affinity for the phenylalkylamine binding site of the calcium channel and in vitro sensitization of resistant cells. In vivo, when administered po in association with vincristine (0.25 mg/kg), five compounds (3, 4, 9, 25, and 26), of very differing calcium channel affinities (Ki from 5 to 560 nM), fully restored (T/V > or = 1.4) the sensitivity of P388/VCR leukemia to vincristine.

In vivo evidence of complete circumvention of vincristine resistance by a new triazinoaminopiperidine derivative S 9788 in P388/VCR leukemia model.

S 9788, a new triazinoaminopiperidine derivative, was found to be a potent reversant of vincristine resistance in the in vivo murine leukemic P388/VCR model. In two treatment regimens (Q4D days 1, 5 and 9 and QD days 1-9), S 9788 enhanced the antitumor activity of vincristine in a dose-dependent manner, resulting in a complete circumvention of drug resistance for well-tolerated doses of S 9788. S 9788 was also effective in enhancing therapeutic effects of vincristine in the treatment of sensitive P388-bearing mice. These results strongly suggest that S 9788 may be a potential candidate for circumvention of multidrug resistance (MDR) in clinical practice.

Protective effect of S12340 on cardiac cells exposed to oxidative stress.

Oxidative stress induced by reactive oxygen species is one aspect of the deleterious mechanisms involved in myocardial post-ischemic reperfusion injury. The antioxidant properties of the new molecule S12340 (8-[3-(3,5-diterbutyl-4-hydroxyphenyl-thio)propyl]-1-oxa-2- oxo-3,8-diazaspiro[4.5]decane) were evaluated using three successive in vitro approaches mimicking the cardiac cell damages induced by reactive oxygen species released into the reperfused myocardium. (i) The effects of S12340 on lipid peroxidation were evaluated using an original cell-free model of non-enzymatic peroxidation of 1.32 mM arachidonic acid induced by reactive oxygen species generated photochemically. S12340 (13.2 microM) inhibited by 29% the rate of oxidative fragmentation of monohydroperoxidized arachidonic acid into aldehydic products. (ii) S12340 (10 microM) inhibited by 96% and 58% the oxidative necrosis of cultured rat cardiomyocytes induced by xanthine oxidase (20 mU/ml) and monohydroperoxidized arachidonic acid (30 microM), respectively. (iii) Superfusion of guinea-pig papillary muscle with monohydroperoxidized arachidonic acid (20 microM) resulted in marked alterations of their electrophysiological and mechanical activities. These modifications, maximal 15-17 min after the addition of lipid hydroperoxide, were completely abolished by S12340 (30 microM).

Risk factors associated with alpine skiing injuries in children. A case-control study.

We investigated the relative contribution of four risk factors to the occurrence of injuries among alpine skiers aged 12 years and younger (3 to 12 years old; mean age, 9.43 years). The risk factors selected were deficient binding adjustment, absence of formal training, low skill level, and use of rented equipment. A group of injured skiers (N = 41) and a control group of uninjured skiers (N = 313) were recruited among young skiers at one major alpine ski center in the Quebec City, Canada, area during the 1995 to 1996 season. No significant group differences were found for mean age or sex distribution. The adjusted odds ratios for injury were 7.54 (95% confidence interval [2.57, 22.15]) for skiers in the low level of skill category relative to highly skilled skiers, 7.14 (2.59, 19.87) for skiers who rented their ski equipment compared with skiers who owned their equipment, and 2.11 (1.02, 4.33) for skiers with ill-adjusted bindings compared with skiers with better-adjusted bindings. Only formal training did not meet the 0.05 significance level for entry into the model; this is probably because of methodologic limitations. Implications of these results for the development of a prevention program aimed at young skiers are discussed.

[The almitrine dimesylate molecule. Various structure-activity relationship aspects]. / La molécule de bismésilate d'almitrine. Quelques aspects des relations structure-activité.

The improvement in PaO2 induced by almitrine bismesylate is due to better adjustment between alveolar ventilation and lung perfusion (VA/Q ratio). Experimental studies and clinical pharmacology suggest that this improvement involves changes in both alveolar ventilation and pulmonary circulation. By synthesizing and testing compounds with different structures in a series of trisubstituted triazines, it has been possible to determine qualitative structure-activity relationships and to select almitrine bismesylate is due to better adjustment between the greatest, most rapid and longest lasting increase in PaO2. Almitrine bismesylate is a molecule with three components: a di-allylamino-triazine group, a piperazine ring and a bis-parafluoro-benzhydryl fraction. The di-allylamino-triazine group may be regarded as responsible for the effects on blood gases and ventilation. The presence of two allyl-amino substituents is an absolute prerequisite, and the triazine ring can possibly be replaced by a very similar pyrimidine ring. The piperazine ring is mainly responsible for dissociation between the effects on blood gases and on ventilation as well as for the general kinetics of the biological action of the drug. Molecules of this series which have a pyrrolidine ring or an azetidine ring instead of a piperazine ring do increase PaO2 but much more slowly than almitrine bismesilate. Finally, the bis-parafluoro-benzhydryl group modulates the intensity and duration of the effects on blood gases. Other constituents, such as the cinnamylamino, alpha-cyclohexyl-parafluorobenzyl, beta-naphthyl methyl or 5-fluoro-benzofluranyl-methyl groups also exert favourable biological activities comparable to those of the bis-parafluorobenzhydryl group characteristic of almitrine bismesylate.

[Pharmacological studies of a new antitussive, 1-phenethyl-4-hydroxy-salicylamido-4-methyl-piperidine-hydrochloride (S 1592) (author's transl)]. / Etudes pharmacologiques d'un nouvel antitussif: le phénéthyl-1 hydroxy-4 salicylamido méthyl-4 pipéridine, chlorhydrate (S 1592)

1-Phenethyl-4-hydroxy-salicylamido-4-methylpiperidine-hydrochloride (S 1592) markedly inhibits coughing induced in laboratory animals by chemical or mechanical irritation of respiratory tract or by electrical stimulation of the superior laryngeal nerve. The drug has low acute toxicity in mice and rats. The new compound possesses bronchodilating and antianaphylactic properties and does not affect gastrointestinal propulsion. Cardiovascular effects are absent.

Almitrine bismesylate: pharmacological review and structure-activity relationships.

In the anaesthetized dog almitrine bismesylate (A) increases ventilation after i.v. injections of more than 100 ug X kg-1. This ventilatory stimulation is due to the specific agonistic action of A on the peripheral chemoreceptors. With lower doses of A no modification of ventilation is recorded even though PaO2 significantly increases. The mechanisms by which A induces pulmonary gas exchange improvement are not clearly demonstrated. A long lasting potentiation of local hypoxic pulmonary vasoconstriction was initially postulated but more recent experimental results recorded on animals with heterogeneously ventilated lungs do not support this hypothesis. However, a redistribution of pulmonary blood flow due to the transient vasoconstrictor effect of A cannot be excluded: it might divert the blood from the well perfused lung bases towards the less well perfused lung apex. Other authors have demonstrated that undetected small ventilatory changes might improve alveolar ventilation and raise PaO2. The almitrine bismesylate molecule is a successful example of pharmacochemical research applied to bronchopulmonary pathology. By using qualitative structure activity relationships it has been possible to choose from a series of triazine derivatives, this remarkable molecule, exerting a clear tropism for the pulmonary tract with a dual effect improving both ventilatory and gasometric parameters through peripheral chemoreceptor stimulation, and characterized by a rapid onset of action and a durable activity. In this respect, the di-allyl-amino-triazine moiety may be considered as an inducer of gasometric and ventilatory effects. The piperazine nucleus is mainly responsible for the ventilatory/gasometric dissociation and for the kinetics of these pulmonary actions. Finally, the bisparafluorobenzydryl component is a 'modulator' of intensity of gasometric effects.

[Arterial time of intravenous pyelography: initial results (author's transl)]. / Temps artériel de l'urographie intraveineuse. Premiers résultats

The authors consider that attention should be paid to the arterial time in intravenous pyelography in all patients who undergo the examination. Manual injection or an injector containing 80 to 100 ml of 38% iodine contrast medium set at a speed of 20 ml/sec, on the one hand, and films taken during the arterial phase on the other hand, are the two conditions necessary to obtain a satisfactory arteriogram. Slight abdominal compression and subtraction improve the definition of the films. 600 cases have been collected so far, in the exploration of 105 patients with hypertension, 17 cysts, 7 malignant tumours, extra-renal pathology and various nephropathies in which no indication for arteriography existed. Thus pyelographic arteriography made it possible to avoid renal arteriograms in almost all our patients. Only one selective and one complete arteriogram were necessary. Unusual arterial lesions in nonsurgical renal conditions may be seen (glomerulonephritis, nephroangiosclerosis...) and unexpected images in abdominal conditions with renal manifestations or in association with nephropathies (aneurysms of digestive arteries and the aorta, collagen diseases etc.).

Health technology assessment and the regulation of medical devices and procedures in Quebec. Synergy, collusion, or collision?

In this paper, we discuss the complex relationship between health technology assessment (HTA) and the regulation of medical devices and procedures. The relationship is first examined through a conceptual framework describing the itinerary from research to three levels of policy making: micro (standards of medical practice), meso (institutional rules), and macro (health policies). Four reports from the Quebec Health Technology Assessment Council (CETS) are used to illustrate how HTA activities can influence the regulatory mechanisms operating at each decision-making level. We then discuss the skillful balancing act required from HTA agencies to constantly negotiate the right distance from the regulatory process at which to operate. We propose that HTA agencies should not be incorporated into any regulatory, auditing, or monitoring process. Finally, the relationship between health technology assessment and health care reform is discussed. It is suggested that HTA activities will contribute most during the data-driven preparation and consolidation phases of a reform process. The fast pace of events and the political turmoil characteristic of the implementation phase provide a less receptive environment for HTA contributions.

Pharmacological properties of a new antiasthmatic xanthine derivative devoid of central stimulatory activity.

The bronchodilating effect and other related pharmacological properties of an 8-amino alkyl substituted xanthine (S 9795) were compared with those of reference drugs, in particular theophylline. The in vitro studies using the tracheal ring, taenia coli, rat peritoneal mastocytes and enzymic preparations demonstrated the potency of S 9795 as an antiasthmatic drug, possessing protective activity superior to that of theophylline and enprofylline. S 9797 was 100 times more active as a cAMP phosphodiesterase inhibitor than theophylline. The compound also protected against mast cell degranulation and consequent release of spasmogen due to antigen-antibody reaction or induced by Ca2+ movements. Given orally or intravenously. S 9795 had a highly selective protective effect against bronchoconstriction induced by pharmacological reagents or allergic reactions with no demonstrable effect on the central nervous or cardiovascular systems. The pharmacological effects of S 9795 were of longer duration than those of theophylline and enprofylline. These studies demonstrate the potential therapeutic value of S 9795 in the therapy of bronchospastic disorders.

S 12340: a potent inhibitor of the oxidative modification of low-density lipoprotein in vitro and ex vivo in WHHL rabbits.

Oxidative modification of low-density lipoprotein (LDL) is thought to play a key role in the formation of foam cells and in the initiation and progression of the atherosclerotic plaque. After evaluation of a large number of original drugs, S 12340 was found to be the most potent compound in inhibiting in a dose-dependent manner the human LDL oxidative modification induced either by copper ions or by cultured endothelial cells. Both the electrophoretic mobility and the thiobarbituric acid reactive substances returned to almost normal values in the presence of 0.5 microM of S 12340. Watanabe heritable hyperlipidemic rabbits were treated orally for 3 days or for 1 month with S 12340 to evaluate the potential protective effect of the compound on LDL oxidative modification induced ex vivo. Purified LDL from placebo and treated rabbits were submitted to oxidation, and S 12340 was effectively able to protect LDL in a dose-dependent manner and at doses as low as 10 mg/kg/day. Purified LDL from animals sacrificed at various times after oral administration of S 12340 were protected against oxidation for at least 6 h after the last administration of the compound. These findings are in good agreement with the plasma and LDL levels of S 12340 in these WHHL rabbits. S 12340, probucol and vitamin E were all able to decrease the optical density of the 1,1-diphenyl-2-picrylhydrazyl solution, demonstrating their free radical scavenging properties. The pharmacological properties of the compound suggest that S 12340 may be of potential interest for a new therapeutic approach to atherosclerosis.

In vitro and in vivo circumvention of multidrug resistance by Servier 9788, a novel triazinoaminopiperidine derivative.

S 9788 is a novel triazinoaminopiperidine derivative which does not belong to any of the classes of compounds known to reverse multidrug resistance (MDR). S 9788 was far more potent than verapamil (VRP) in reversing resistance to adriamycin (ADR) in the ADR-selected murine leukaemia cell lines P388/ADR-1 and P388/ADR-10, and the human chronic myelogenous leukaemia K562/R. Fold reversion with S 9788 (5 microM) was, respectively, 3.5, 5.4 and 11.3 times greater than that with VRP (5 microM). S 9788 was also a more potent reversant of ADR resistance in the intrinsically resistant human colon adenocarcinoma COLO 320DM (2.3 fold), and of vincristine (VCR) resistance in the human MDR1 gene-transfected squamous lung carcinoma line S1/tMDR1 (5.6 fold). The activity of S 9788 depended on both the MDR cell line and the cytotoxic agent. S 9788 (50-100 mg/kg/d) administered IP once a day on days 1-4 resulted in a dose-dependent increase in the chemotherapeutic effect of VCR (0.25 mg/kg/d) in P388/VCR - bearing mice and ADR (4 mg/kg/d) in P388/ADR - bearing mice. Increases in antitumor activity were (% T/C) of +20-34% in the P388/ADR model and + 50-78% in the P388/VCR model with respect to cytotoxic agent treatment alone. S 9788 appeared to be devoid of toxicity at its effective doses. The mechanism of action of S 9788 is unknown but S 9788 (0.5-10 microM) induced a dose-dependent increase in ADR accumulation in KB-Al cells and compared to verapamil its effect was twice as active and approximately seven times more potent. We conclude that S 9788 is a novel agent capable of reversing MDR in vitro and in vivo, and whose pharmacological profile warrants its selection as a candidate drug for eventual assessment in the clinic.